COP1/DET1/ETS axis regulates ERK transcriptome and sensitivity to MAPK inhibitors

Area of Science:

• Oncology
• Molecular Biology
• Signal Transduction

Background:

• Aberrant activation of Mitogen-Activated Protein Kinase (MAPK) signaling is a hallmark of many cancers, leading to the expression of oncogenic transcriptomes.
• The precise mechanisms linking MAPK signaling to transcriptional responses in cancer remain incompletely understood.
• ETV1 and other Pea3-ETS transcription factors are identified as crucial nuclear effectors of MAPK signaling.

Purpose of the Study:

• To elucidate how MAPK signaling is coupled with transcriptional responses in cancer.
• To identify key regulators of ETV1 and Pea3-ETS protein stability in MAPK-activated tumors.
• To investigate the role of protein stability in therapeutic resistance to MAPK pathway inhibitors.

Main Methods:

• Performed a pooled genome-wide RNAi screen utilizing a fluorescence-based ETV1 protein stability sensor.
• Investigated the impact of COP1 or DET1 loss on MAPK signaling and downstream transcriptional output.
• Analyzed mutations in COP1 and DET1 in human tumors and their functional consequences on Pea3-ETS factor degradation.

Main Results:

• ETV1 and Pea3-ETS factors are critical nuclear effectors of MAPK signaling, regulated by protein stability.
• Loss of COP1 or DET1 decoupled MAPK signaling from the transcriptional response, impairing MAPK inhibitor efficacy.
• Identified mutations in COP1 and DET1 in human tumors that confer resistance to MAPK inhibitors, including de novo mutations in melanoma patients post-treatment.

Conclusions:

• MAPK signaling-dependent regulation of Pea3-ETS protein stability is a critical node in oncogenesis.
• Dysregulation of Pea3-ETS protein stability contributes to therapeutic resistance in MAPK-driven cancers.
• Targeting the COP1/DET1-mediated degradation pathway may offer strategies to overcome resistance to MAPK inhibitors.